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The ubiquitination status of the glucagon receptor determines signal bias.

Publication ,  Journal Article
Kaur, S; Sokrat, B; Capozzi, ME; El, K; Bai, Y; Jazic, A; Han, B; Krishna Kumar, K; D'Alessio, DA; Campbell, JE; Bouvier, M; Shenoy, SK
Published in: J Biol Chem
May 2023

The pancreatic hormone glucagon activates the glucagon receptor (GCGR), a class B seven-transmembrane G protein-coupled receptor that couples to the stimulatory heterotrimeric G protein and provokes PKA-dependent signaling cascades vital to hepatic glucose metabolism and islet insulin secretion. Glucagon-stimulation also initiates recruitment of the endocytic adaptors, βarrestin1 and βarrestin2, which regulate desensitization and internalization of the GCGR. Unlike many other G protein-coupled receptors, the GCGR expressed at the plasma membrane is constitutively ubiquitinated and upon agonist-activation, internalized GCGRs are deubiquitinated at early endosomes and recycled via Rab4-containing vesicles. Herein we report a novel link between the ubiquitination status and signal transduction mechanism of the GCGR. In the deubiquitinated state, coupling of the GCGR to Gs is diminished, while binding to βarrestin is enhanced with signaling biased to a βarrestin1-dependent p38 mitogen activated protein kinase (MAPK) pathway. This ubiquitin-dependent signaling bias arises through the modification of lysine333 (K333) on the cytoplasmic face of transmembrane helix V. Compared with the GCGR-WT, the mutant GCGR-K333R has impaired ubiquitination, diminished G protein coupling, and PKA signaling but unimpaired potentiation of glucose-stimulated-insulin secretion in response to agonist-stimulation, which involves p38 MAPK signaling. Both WT and GCGR-K333R promote the formation of glucagon-induced βarrestin1-dependent p38 signaling scaffold that requires canonical upstream MAPK-Kinase3, but is independent of Gs, Gi, and βarrestin2. Thus, ubiquitination/deubiquitination at K333 in the GCGR defines the activation of distinct transducers with the potential to influence various facets of glucagon signaling in health and disease.

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Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

May 2023

Volume

299

Issue

5

Start / End Page

104690

Location

United States

Related Subject Headings

  • Ubiquitination
  • Receptors, Glucagon
  • Liver
  • Humans
  • HEK293 Cells
  • Glucose
  • Glucagon
  • Biochemistry & Molecular Biology
  • 34 Chemical sciences
  • 32 Biomedical and clinical sciences
 

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Kaur, S., Sokrat, B., Capozzi, M. E., El, K., Bai, Y., Jazic, A., … Shenoy, S. K. (2023). The ubiquitination status of the glucagon receptor determines signal bias. J Biol Chem, 299(5), 104690. https://doi.org/10.1016/j.jbc.2023.104690
Kaur, Suneet, Badr Sokrat, Megan E. Capozzi, Kimberley El, Yushi Bai, Aeva Jazic, Bridgette Han, et al. “The ubiquitination status of the glucagon receptor determines signal bias.J Biol Chem 299, no. 5 (May 2023): 104690. https://doi.org/10.1016/j.jbc.2023.104690.
Kaur S, Sokrat B, Capozzi ME, El K, Bai Y, Jazic A, et al. The ubiquitination status of the glucagon receptor determines signal bias. J Biol Chem. 2023 May;299(5):104690.
Kaur, Suneet, et al. “The ubiquitination status of the glucagon receptor determines signal bias.J Biol Chem, vol. 299, no. 5, May 2023, p. 104690. Pubmed, doi:10.1016/j.jbc.2023.104690.
Kaur S, Sokrat B, Capozzi ME, El K, Bai Y, Jazic A, Han B, Krishna Kumar K, D’Alessio DA, Campbell JE, Bouvier M, Shenoy SK. The ubiquitination status of the glucagon receptor determines signal bias. J Biol Chem. 2023 May;299(5):104690.

Published In

J Biol Chem

DOI

EISSN

1083-351X

Publication Date

May 2023

Volume

299

Issue

5

Start / End Page

104690

Location

United States

Related Subject Headings

  • Ubiquitination
  • Receptors, Glucagon
  • Liver
  • Humans
  • HEK293 Cells
  • Glucose
  • Glucagon
  • Biochemistry & Molecular Biology
  • 34 Chemical sciences
  • 32 Biomedical and clinical sciences